PROJECT SUMMARY Brain aneurysms are a high-risk condition in which bulging blood vessels in the brain are at risk of rupture. The mortality rate after rupture is 40-60% if no treatment is administered. Current treatment for both ruptured and unruptured aneurysms includes surgical clipping (exovascular therapy) and catheter-based intervention (endovascular therapy). In endovascular therapy, which is the focus of this work, platinum coils are inserted into the aneurysm to induce clotting and exclude the aneurysm from circulation. The primary challenge associated with endovascular aneurysm therapy is the risk of aneurysm recurrence due to mechanical compaction and enzymatic digestion of the clot in the aneurysm sac. Recurrence in intracranial aneurysms elevates the risk of hemorrhagic stroke. This proposal will evaluate the safety and efficacy of a drug-eluting coil to improve outcomes when treating intracranial aneurysms prophylactically. We posit that sustained release of naturally occurring crosslinking agents delivered from drug-eluting endovascular coils will increase the mechanical robustness of the clots, reduce fibrinolysis, and ultimately reduce the risk of recurrence. Clots with increased chemo-mechanical stability will resist failure modes associated with coil compaction and enzymatic degradation. The safety and efficacy of genipin-eluting coils will be evaluated in animal models that are clinically relevant and mimic the anatomy of defects in humans. The safety and efficacy of genipin-eluting coils will be evaluated as a function of dosing and delivery kinetics. In vitro efficacy will be measured using a simulated coiled aneurysm in a model aneurysm sac operating under perfusion. In vivo experiments will be performed using a rabbit elastase aneurysm model. Efficacy will be quantified by angiography, histology, and chemo-mechanical measurements of thrombus in the aneurysms. This project will ultimately measure the in vivo safety and efficacy of drug-eluting coils as a potentially superior technology to treat unruptured anuerysms. Follow-on clinical studies in humans will further establish the safety and efficacy of genipin-eluting embolization coils. Drug-eluting coils have the potential to transform the treatment of unruptured intracranial aneurysms and dramatically reduce the risk of hemorrhagic stroke.